The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

A Descriptive Introduction to Human Aging
must understand not only why cells that die are not replaced, but also why they die in the
first place. But there is no reason to seek a single reason for this low-rate, steady cells death—the
most obvious theory, that they die of a wide variety of causes due to simply living for a long
time in a relatively unstable environment, is enough. Also, cells become more sensitive to
stress as we age: 22,23 liver cells isolated from elderly individuals are more prone to die from a
given degree of stress than cells of the same type isolated from younger people.*
Does this group of symptoms of aging have anything in common with atherosclerosis
and cancer? Indeed it does. The efficacy of the various cellular functions touched on above
will be diminished if the proteins that perform them are damaged, and LECs can damage all
these proteins, just as they damage those that perform DNA maintenance. The ability of a
cell to survive stress of various kinds is, likewise, dependent on its ability rapidly to synthesise
the proteins that protect it; if many of these proteins (or those involved in their construction)
are damaged, that ability is correspondingly reduced.
5.4. Blindness
We saw in the previous section that cells recycle their internal protein and lipid quite
rapidly, in contrast to the rather slow and imperfect recycling of extracellular proteins.
Much of the intracellular recycling is done in lysosomes, which are the generic garbage
collector of the cell. One of the first age-related changes to be discovered inside cells was
that lysosomes gradually accumulate a fluorescent pigment, which is called lipofuscin. 26,27
Lipofuscin proved rather hard to characterise chemically, but there is now a consensus that
it comprises highly heterogeneous polymers of protein and lipid, together with a substantial
concentration of metal ions which were presumably once the cofactors of some of the
proteins. It is believed to result from a feature of LEC-mediated oxidation reactions: namely,
that the products of oxidation are enormously varied (see Section 3.8). Lysosomes contain
a huge variety of destructive enzymes, capable of breaking down all manner of protein and
lipid molecules (and their modified forms resulting from peroxidation) into their
small-molecule constituents, but it is simply not possible to have an enzyme for everything.
Some of the molecular knots tied by peroxidation will thus be too Gordian for lysosomes
to unravel. Lipofuscin has just the characteristics that would be expected of this indigestible
remnant: a granule in which such molecules are packaged up out of harm’s way, and never
need to be properly disposed of. Since the indigestible products are very rare, resulting
only from particularly complex sequences of reactions, they never reach levels that cause
the cell any inconvenience.**
Except, that is, in the retina. There, protein turnover is probably just as efficient as
anywhere else—that is, the proportion of protein and lipid that lysosomes are unable to
digest is just as small—but what is different is the amount of protein and lipid that must be
recycled. The absorption of light by rhodopsin is an extremely protein-damaging process,
* It should be noted that there are also reliable reports of the opposite effect: of cells becoming progressively
less prone to die when stressed. 24,25 But there is in fact no conflict of data, because this resistance to death is
a feature of cells in culture that have replicated many times more than they are ever required to in the body
and have become unable to replicate any more—have reached replicative senescence. This happens because
the type of cell death that these stressed cells undergo—apoptosis—is not simply atrophy: it is a program, very
rigorously controlled by a complex series of genetic interactions, and replicative senescent cells have lost not
only the ability to divide but also the ability to perform some of these interactions. Put simply, they want to
die but they can’t. We will come back to replicative senescence in Section 7.3 and to apoptosis in Chapter 14.
** It is not in fact certain that lipofuscin is as harmless as this. One possibility 28,29 is that it harms us passively,
by "distracting" lytic enzymes in lysosomes. In vivo evidence for this is still lacking, however.
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